Pharmacokinetic Analysis of an Isoniazid Suspension Among Spanish Children Under 6 Years of Age
<b>Background</b>: Isoniazid (INH) remains a first-line drug for the treatment of tuberculosis (TB) in young children. In 2010, the WHO recommended an increase in the daily dose of INH up to 10 (7–15) mg/kg. Currently, there are no INH suspensions available in Europe. <b>Methods<...
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2025-01-01
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| author | Antoni Noguera-Julian Emma Wilhelmi Maria Cussó Rob Aarnoutse Angela Colbers Loreto Martorell Maria Goretti López-Ramos Joan Vinent Rosa Farré Dolors Soy Sílvia Simó-Nebot Clàudia Fortuny |
| author_facet | Antoni Noguera-Julian Emma Wilhelmi Maria Cussó Rob Aarnoutse Angela Colbers Loreto Martorell Maria Goretti López-Ramos Joan Vinent Rosa Farré Dolors Soy Sílvia Simó-Nebot Clàudia Fortuny |
| author_sort | Antoni Noguera-Julian |
| collection | DOAJ |
| description | <b>Background</b>: Isoniazid (INH) remains a first-line drug for the treatment of tuberculosis (TB) in young children. In 2010, the WHO recommended an increase in the daily dose of INH up to 10 (7–15) mg/kg. Currently, there are no INH suspensions available in Europe. <b>Methods</b>: We aimed to characterize the pharmacokinetics of a licensed INH suspension (10 mg/mL, Pharmascience Inc., Montreal, QC, Canada) in children receiving INH daily at 10 mg/kg in a single-center, open-label, non-randomized, phase IIa clinical trial (EudraCT Number: 2016-002000-31) in Barcelona (Spain). Samples were analyzed using a validated UPLC-UV assay. The <i>N</i>-acetyltransferase 2 gene was examined to determine the acetylation status. A non-compartmental pharmacokinetic analysis was conducted. <b>Results</b>: Twenty-four patients (12 females) were included (primary chemoprophylaxis, <i>n</i> = 12; TB treatment, <i>n</i> = 9; and TB infection preventive treatment, <i>n</i> = 3). The acetylator statuses were homozygous fast (<i>n</i> = 3), heterozygous intermediate (<i>n</i> = 18), and homozygous slow (<i>n</i> = 2; unavailable in one patient). The INH median (IQR) C<sub>max</sub> and AUC<sub>0–24h</sub> values were 6.1 (4.5–8.2) mg/L and 23.0 (11.2–35.4) h∙mg/L; adult targets (>3 mg/L and 11.6–26.3 h∙mg/L) were not achieved in three and six cases, respectively. Gender, age at assessment (<2 or >2 years), and INH monotherapy (vs. combined TB treatment) had no impact on pharmacokinetic parameters. Significant differences in C<sub>max</sub> (<i>p</i> = 0.030) and AUC<sub>0–24h</sub> (<i>p</i> = 0.011) values were observed based on acetylator status. Treatment was well tolerated, and no severe adverse events were observed; three patients developed asymptomatic mildly elevated alanine aminotransferase levels. <b>Conclusions</b>: In infants and children receiving a daily INH suspension at 10 mg/kg, no safety concerns were raised, and the target adult levels were reached in the majority of patients. |
| format | Article |
| id | doaj-art-fac67770d02b4f2698219fdb34a933a9 |
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| language | English |
| publishDate | 2025-01-01 |
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| spelling | doaj-art-fac67770d02b4f2698219fdb34a933a92025-01-24T13:18:52ZengMDPI AGAntibiotics2079-63822025-01-011417410.3390/antibiotics14010074Pharmacokinetic Analysis of an Isoniazid Suspension Among Spanish Children Under 6 Years of AgeAntoni Noguera-Julian0Emma Wilhelmi1Maria Cussó2Rob Aarnoutse3Angela Colbers4Loreto Martorell5Maria Goretti López-Ramos6Joan Vinent7Rosa Farré8Dolors Soy9Sílvia Simó-Nebot10Clàudia Fortuny11Malalties Infeccioses i Resposta Inflamatòria Sistèmica en Pediatria, Servei d’Infectologia, Institut de Recerca Pediàtrica Sant Joan de Déu, 08950 Barcelona, SpainPharmacy Department, Hospital Sant Joan de Déu, 08950 Barcelona, SpainMalalties Infeccioses i Resposta Inflamatòria Sistèmica en Pediatria, Servei d’Infectologia, Institut de Recerca Pediàtrica Sant Joan de Déu, 08950 Barcelona, SpainDepartment of Pharmacy, Radboud University Medical Center, Radboud Institute for Health Sciences, 6525 GA Nijmegen, The NetherlandsDepartment of Pharmacy, Radboud University Medical Center, Radboud Institute for Health Sciences, 6525 GA Nijmegen, The NetherlandsMolecular Genetics Department, Hospital Sant Joan de Déu, 08950 Barcelona, SpainPharmacy Department, Hospital Sant Joan de Déu, 08950 Barcelona, SpainPharmacy Department, Hospital Sant Joan de Déu, 08950 Barcelona, SpainPharmacy Department, Hospital Sant Joan de Déu, 08950 Barcelona, SpainPharmacy Department, Division of Medicines, Hospital Clinic of Barcelona, University of Barcelona, 08036 Barcelona, SpainMalalties Infeccioses i Resposta Inflamatòria Sistèmica en Pediatria, Servei d’Infectologia, Institut de Recerca Pediàtrica Sant Joan de Déu, 08950 Barcelona, SpainMalalties Infeccioses i Resposta Inflamatòria Sistèmica en Pediatria, Servei d’Infectologia, Institut de Recerca Pediàtrica Sant Joan de Déu, 08950 Barcelona, Spain<b>Background</b>: Isoniazid (INH) remains a first-line drug for the treatment of tuberculosis (TB) in young children. In 2010, the WHO recommended an increase in the daily dose of INH up to 10 (7–15) mg/kg. Currently, there are no INH suspensions available in Europe. <b>Methods</b>: We aimed to characterize the pharmacokinetics of a licensed INH suspension (10 mg/mL, Pharmascience Inc., Montreal, QC, Canada) in children receiving INH daily at 10 mg/kg in a single-center, open-label, non-randomized, phase IIa clinical trial (EudraCT Number: 2016-002000-31) in Barcelona (Spain). Samples were analyzed using a validated UPLC-UV assay. The <i>N</i>-acetyltransferase 2 gene was examined to determine the acetylation status. A non-compartmental pharmacokinetic analysis was conducted. <b>Results</b>: Twenty-four patients (12 females) were included (primary chemoprophylaxis, <i>n</i> = 12; TB treatment, <i>n</i> = 9; and TB infection preventive treatment, <i>n</i> = 3). The acetylator statuses were homozygous fast (<i>n</i> = 3), heterozygous intermediate (<i>n</i> = 18), and homozygous slow (<i>n</i> = 2; unavailable in one patient). The INH median (IQR) C<sub>max</sub> and AUC<sub>0–24h</sub> values were 6.1 (4.5–8.2) mg/L and 23.0 (11.2–35.4) h∙mg/L; adult targets (>3 mg/L and 11.6–26.3 h∙mg/L) were not achieved in three and six cases, respectively. Gender, age at assessment (<2 or >2 years), and INH monotherapy (vs. combined TB treatment) had no impact on pharmacokinetic parameters. Significant differences in C<sub>max</sub> (<i>p</i> = 0.030) and AUC<sub>0–24h</sub> (<i>p</i> = 0.011) values were observed based on acetylator status. Treatment was well tolerated, and no severe adverse events were observed; three patients developed asymptomatic mildly elevated alanine aminotransferase levels. <b>Conclusions</b>: In infants and children receiving a daily INH suspension at 10 mg/kg, no safety concerns were raised, and the target adult levels were reached in the majority of patients.https://www.mdpi.com/2079-6382/14/1/74acetylator statuschildisoniazidpharmacokineticssuspensiontuberculosis |
| spellingShingle | Antoni Noguera-Julian Emma Wilhelmi Maria Cussó Rob Aarnoutse Angela Colbers Loreto Martorell Maria Goretti López-Ramos Joan Vinent Rosa Farré Dolors Soy Sílvia Simó-Nebot Clàudia Fortuny Pharmacokinetic Analysis of an Isoniazid Suspension Among Spanish Children Under 6 Years of Age Antibiotics acetylator status child isoniazid pharmacokinetics suspension tuberculosis |
| title | Pharmacokinetic Analysis of an Isoniazid Suspension Among Spanish Children Under 6 Years of Age |
| title_full | Pharmacokinetic Analysis of an Isoniazid Suspension Among Spanish Children Under 6 Years of Age |
| title_fullStr | Pharmacokinetic Analysis of an Isoniazid Suspension Among Spanish Children Under 6 Years of Age |
| title_full_unstemmed | Pharmacokinetic Analysis of an Isoniazid Suspension Among Spanish Children Under 6 Years of Age |
| title_short | Pharmacokinetic Analysis of an Isoniazid Suspension Among Spanish Children Under 6 Years of Age |
| title_sort | pharmacokinetic analysis of an isoniazid suspension among spanish children under 6 years of age |
| topic | acetylator status child isoniazid pharmacokinetics suspension tuberculosis |
| url | https://www.mdpi.com/2079-6382/14/1/74 |
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